The press invention relates to stable amorphous forms of montelukast sodium and, more particularly, to stable amorphous forms of montelukast sodium which are suitable for use in the preparation of solid dosage formulations, to processes of preparing same, to compositions containing the same and to methods of treatment using the same.
(R-(E)-1-(((1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid sodium salt, also known by the name montelukast sodium, is represented by Formula I below:

Montelukast is freely soluble in ethanol, methanol and water but is practically insoluble in acetonitrile.
Montelukast sodium is a leukotriene antagonist, and is thus useful as an anti-asthmatic, anti-allergic, ant-inflammatory and cytoprotective agent. Montelukast sodium is currently indicated for the treatment of allergic rhinitis and asthma.
Montelukast sodium, formulated as tablets (containing 10.4 mg montelukast sodium), chewable tablets (containing 4.2 or 5.2 mg montelukast sodium) or oral granules (in a packet containing 4.2 mg montelukast sodium), is typically given once daily to the patients for the treatment of asthma and seasonal allergic rhinitis. Montelukast sodium is marketed in the United States and other countries by Merck & Co., Inc. under the trade name Singulair®.
However, the form of montelukast sodium used in preparing Singulair® is hygroscopic and therefore require special care in handling and storage, which adversely affect the efficiency of the production process.
Montelukast sodium and related compounds were first disclosed in European Patent No. EP 480,717. The synthesis of montelukast sodium, as taught in EP 480,717, involves coupling methyl 1-(mercaptomethyl)cyclopropaneacetate with (S)-1-(3-(2-(7-chloro-2-quinolinyl)ethyl(phenyl)-3(-2-(1-hydroxy-1-methylethyl)phenyl)propyl-methanesulfonate, followed by hydrolysis of the resulting methyl ester so as to form a free acid, which is followed by conversion of the free acid to a corresponding sodium salt. The sodium salt is prepared in an aqueous solution and the water is removed by freeze-drying.
International Patent Application published as WO 95/18107 teaches a method for the preparation of crystalline montelukast sodium, which involves the preparation of the dilithium dianion of 1-(mercaptomethyl) cyclopropaneacetic acid as an intermediate, followed by condensation thereof with 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-methanesulfonyloxypropyl)phenyl)-2-propanol, to yield montelukast acid. The resulting montelukast acid is converted, via the corresponding dicyclohexyl amine salt, to montelukast sodium. The montelukast sodium is crystallized from a toluene/acetonitrile solution to obtain crystalline montelukast sodium. This publication further notes that the compounds disclosed in EP 480,717 are hydrated amorphous montelukast sodium, and are therefore not ideal for use in the formulation of pharmaceutical compositions.
International Patent Application PCT/US03/03700, published as WO 03/066598, discloses an anhydrous amorphous form of montelukast sodium. The amorphous montelukast sodium is prepared, according to the teachings of WO 03/066598, by providing a solution of montelukast free acid in an aromatic solvent; converting the free acid to an alkali salt using methanolic sodium hydroxide; adding a hydrocarbon solvent, and isolating the thus obtained amorphous montelukast sodium. Preparing amorphous montelukast sodium by flocculation from aromatic and hydrocarbon solvents is disadvantageous, particularly when compared to aqueous solutions, due to the toxicity, cost and typical hazardousness of such organic solvents.
In recent years, solid-state properties of drugs received a great focus in the pharmaceutical industry, as a major contributing factor to both bioavailability and formulation characteristics. The ability of some substances to exist in more than one form, whether crystalline or amorphous, was accredited as one of the most important solid-state property of drugs. While different chemical forms have the same chemical composition, they differ in the packing and geometrical arrangement thereof, and exhibit different physical properties such as melting point, shape, color, density, hardness, deformability, stability, dissolution, and the like.
General background and theory of forms is found for example in “Effects of Polymorphism and Solid-State Solvation on Solubility and Dissolution Rate”, in Polymorphism in Pharmaceutical Solids, edited by Harry G. Brittain, Drugs and the Pharmaceutical Sciences, Volume 95, MARCEL DEKKER, Inc.; “Effects of Pharmaceutical Processing on Drug Polymorphs and Solvates”, in Polymorphism in Pharmaceutical Solids, edited by Harry G. Brittain; Drugs and the Pharmaceutical Sciences, Volume 95, MARCEL DEKKER, Inc.; “Theoretical approaches to physical transformations of active pharmaceutical ingredients during manufacturing process”, Morris et al, Advanced drug delivery reviews, 48, 2001; and Theory and Origin of Polymorphism in “Polymorphism in Pharmaceutical Solids” (1999) ISBN: 8247-0237.
In some cases, different forms of the same drug can exhibit very different solubility, and therefore different dissolution rates (release profile) in-vivo. It is known, for example, that amorphous forms of some drugs exhibit dissolution characteristics and bioavailability patterns different from corresponding crystalline forms [Konne T., Chem. Pharm. Bull., 38, 2003 1990]. For some therapeutic indications one bioavailability pattern may be favored over another. This phenomenon may be used to create better drugs that dissolve either rapidly or very slowly, according to the specific needs of each formulation. However, any failure to predict the bioavailability of a drug may result in administration of either too small or too large undesired doses, which may be dangerous to patients and in extreme cases, lethal.
Other examples are known, where different forms behave differently during physical processing like milling and pressing. Many process-induced solid-solid transitions of substances are known, that lead to either other crystalline forms or an amorphous form of the substance. The solid-state experts are in a constant search for forms that can withstand physical stress and still retain their original properties.
Different forms of a pharmaceutically useful compound therefore provide opportunities to improve the performance characteristics of a pharmaceutical product. Different forms enlarge the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of an active pharmaceutical ingredient with a desired characteristic. It is well known that new forms of known useful compounds are of utility. Consequently, there is an ongoing search for new forms of known compounds used in pharmaceutical compositions, which may provide for improved performance thereof.
Hence, the prior art teaches hydrated amorphous montelukast sodium, (European Patent No. EP 480,717), which is highly hygroscopic and therefore its usage in solid formulations is inefficient. The prior art further teaches other forms of montelukast sodium, which were aimed at overcoming the limitations associated with the hydrated amorphous montelukast sodium disclosed in EP 480,717. These include, for example, crystalline montelukast sodium and anhydrous amorphous montelukast sodium (as taught in WO 95/18107 and WO 03/066598, respectively). As discussed hereinabove, formulating crystalline forms of substances into pharmaceutical compositions is limited by the instability of the crystalline form during the formulation process (e.g., when high pressure is applied), solubility characteristics of the substance, and other characteristics. As is further discussed hereinabove, the preparation of the anhydrous amorphous montelukast sodium taught in WO 03/066598 involves solvents such as aromatic hydrocarbons, aliphatic and alicyclic hydrocarbons and halogenated hydrocarbons, which are all considered disadvantageous when used in the preparation of medicaments, since they are relatively toxic, cost-inefficient and environmental unfriendly.
There is thus a widely recognized need for, and it would be highly advantageous to have, novel forms of montelukast sodium and improved processes for the preparation thereof, devoid of the above limitations.